小柯机器人

美国耶鲁大学Richard G. Kibbey团队发现，多组织线粒体磷酸烯醇丙酮酸（PEP）循环的增加速改善了全身性代谢健康。2020年11月3日，国际学术期刊《细胞-代谢》发表了这一成果。

在糖尿病的临床前啮齿动物模型中，研究人员发现小分子丙酮酸激酶（PK）激活剂加速了PEP循环，从而改善了胰岛功能和代谢稳态。相反，用PK激活剂治疗不能改善pck2^-/-小鼠的胰岛素分泌。与其他临床促分泌素不同，PK激活不仅可增强胰岛素分泌，同时也具有更高的胰岛素含量和分化标记。除了改善胰岛素分泌外，急性PK激活还使的糖异生缺陷，以减少内源性葡萄糖生成，同时加速红细胞葡萄糖转运。

在喂食HFD的大鼠体内，全身性递送PK激活剂可重塑PK磷酸化、减少肝脏脂肪并改善肝和外周胰岛素敏感性。这些数据为PK激活剂加速PEP周期以改善代谢稳态和胰岛素敏感性提供了临床前依据。

科学家介绍，线粒体GTP（mtGTP）依赖性磷酸烯醇式丙酮酸循环将线粒体PEPCK（PCK2）与肝脏和胰岛中的丙酮酸激酶耦合，以调节葡萄糖稳态。

附：英文原文

Title: Multi-Tissue Acceleration of the Mitochondrial Phosphoenolpyruvate Cycle Improves Whole-Body Metabolic Health

Author: Abudukadier Abulizi, Rebecca L. Cardone, Romana Stark, Sophie L. Lewandowski, Xiaojian Zhao, Joelle Hillion, Lingjun Ma, Raghav Sehgal, Tiago C. Alves, Craig Thomas, Charles Kung, Bei Wang, Stephan Siebel, Zane B. Andrews, Graeme F. Mason, Jesse Rinehart, Matthew J. Merrins, Richard G. Kibbey

Issue&Volume: 2020/11/03

Abstract: The mitochondrial GTP (mtGTP)-dependent phosphoenolpyruvate (PEP) cycle couples mitochondrialPEPCK (PCK2) to pyruvate kinase (PK) in the liver and pancreatic islets to regulate glucose homeostasis. Here, small molecule PK activators accelerated the PEP cycleto improve islet function, as well as metabolic homeostasis, in preclinical rodentmodels of diabetes. In contrast, treatment with a PK activator did not improve insulinsecretion in pck2/ mice. Unlike other clinical secretagogues, PK activation enhanced insulin secretionbut also had higher insulin content and markers of differentiation. In addition toimproving insulin secretion, acute PK activation short-circuited gluconeogenesis toreduce endogenous glucose production while accelerating red blood cell glucose turnover.Four-week delivery of a PK activator in vivo remodeled PK phosphorylation, reduced liver fat, and improved hepatic and peripheralinsulin sensitivity in HFD-fed rats. These data provide a preclinical rationale forPK activation to accelerate the PEP cycle to improve metabolic homeostasis and insulin sensitivity.

DOI: 10.1016/j.cmet.2020.10.006

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30539-8

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
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